BACKGROUND: In recent years, the need to achieve increasingly ambitious therapeutic goals for dyslipidemias has prompted the search for more potent pharmacological agents to lower circulating atherogenic lipoprotein concentrations and enhance reverse cholesterol transport (RCT). While mounting evidence supports the use of 3-hydroxy-3-methylglutaryl coenzyme reductase inhibitors (or statins) as the main stay of therapy for patients requiring lipid modification therapy, many patients remain under-treated or do not achieve the National Cholesterol Education Program (NCEP) recommended goals.1-5 Recognizing new and emerging data, NCEP III recently updated its guidelines to recognize the potential of a more aggressive low density lipoprotein (LDL) goal of <70 mg/dl in patients at high risk of cardiovascular events.3 The Treating to New Targets (TNT) study showed that even in patients with stable coronary artery disease, a goal that is lower than currently recommended, <80 mg/dl, may be desirable in further reducing and/or preventing recurrent cardiovascular events.6 More than 40% of all Americans have LDL levels of 130 mg/dl or higher, and 13 million Americans have coronary artery disease that may benefit from lipid modification therapy. In these individuals, to achieve the optimal LDL goal and to treat other associated lipid abnormalities, including low HDL cholesterol and/or high triglycerides, many patients will likely require combination therapy.3, 7-13 Among the novel therapeutic agents investigated have been selective thyroid hormone analogues. Such agents hold the promise of harnessing the cholesterol-lowering properties of the naturally occurring thyroid hormones, triiodothyronine (T3) and thyroxine (T4), but with greater receptor isoform and tissue specificity that should result in an improved safety profile.14, 15 Unlike statins, thyroid hormones and their analogues, in addition to cholesterol and LDL-lowering effects, may favorably lower lipoprotein (a) (Lp(a)) and triglyceride levels.15-22 Also, because of potential thyroid hormone-mediated genomic and non-genomic effects on the heart, certain populations, such as those with congestive heart failure, may derive dual benefits from use of such thyromimetic treatment.15, 22, 23 1.1.1 Effects of Thyroid Hormone on Lipid Metabolism Dyslipidemia has long been associated with disorders of thyroid metabolism (i.e., hypothyroidism) and to be potentially reversible by thyroid hormone therapy.17, 18, 21 Early autopsy series demonstrated more severe atherosclerosis in individuals with premorbid hypothyroidism.24, 25 In studies of how thyroid hormone status affected radiolabeled lipoprotein kinetics, LDL was found to be cleared less rapidly in hypothyroid animals and man.26 Subsequently, hepatic LDL receptor number27 and mRNA expression28 were shown to be lower in hypothyroid animals. More recently, characterization of the LDL receptor gene promoter has revealed the presence of functionally important T3 regulatory elements.29 In addition to lowering total and LDL cholesterol concentrations in treated hypothyroid patients, thyroid hormone therapy has been shown in some studies to have a favorable impact on particularly atherogenic lipoproteins, including Lp(a)30 and small dense and oxidizable LDL subfractions.31, 32 Finally, thyroid hormone replacement therapy has been shown to decrease apoB100 lipoprotein synthesis with a resulting decrease in Very Low Density Lipoprotein (VLDL) production and hepatic triglyceride production.33 There is now also considerable evidence that thyroid hormone receptor agonists can directly or indirectly affect reverse cholesterol transport, the process by which cholesterol is transported from peripheral cells, including cholesterol-laden endothelial cells in the initial stage of atherosclerosis, to the liver for conversion to bile acids. First, thyroid hormone affects the activity of apoA 1 lipoprotein,34 which plays several critical roles in RCT-generating HDL that transports cholesterol from peripheral tissues to the liver, as both the principal protein constituent of HDL and an activator of lecithin-cholesterol acyltransferase (LCAT), which esterifies cholesterol on the surface of pre-β-HDL. ApoA-I also stabilizes and increases the level of ATP-binding cassette A1 protein (ABCA1), which, in turn, promotes efflux of cholesterol and phospholipids to nascent HDL-particles. Thyroid hormone increases apoA-I gene expression in liver and intestine, in part through a 5' flanking thyroid hormone response element.35, 36 Thyroid hormone has also recently been shown to increased the scavenger class B type I receptor (SR-BI), another regulator of serum HDL concentrations and cholesterol flux, in livers of mice treated with either T3 or GC-1 (a thyroid hormone receptor modulator).37 Finally, thyroid hormones are also known to increase activity of cholesterol 7α-hydroxylase (CYP-7A1)38 which catalyzes the rate-limiting step in bile acid synthesis; in contrast, HMG-CoA reductase inhibitors have the opposite effect. This thyroid hormone-induced increase in CYP-7A1 would be expected to increase bile acid and cholesterol excretion, as has been observed in hyperthyroidism.39 1.1.2 Previous Clinical Research Previous studies have investigated the therapeutic potential of thyromimetic compounds in lipid modification and heart failure.14,15,40 Early clinical investigation focused on dextrothyroxine (D-T4), a D-isomer of thyroxine, which was thought to have similar actions, but produce less tachycardia and myocardial oxygen consumption.40, 41 Although DT4 was commonly used as a cholesterol lowering drug in the 1970s,42 it is no longer used in clinical practice. The therapeutic effects of DT4 were evaluated in the Coronary Drug Project (CDP).